U.S. patent application number 13/154562 was filed with the patent office on 2011-12-15 for solid dispersions containing kinase inhibitors.
This patent application is currently assigned to ABBOTT LABORATORIES. Invention is credited to Lloyd Dias, Yi Gao, Rajeev Gokhale, Justin Lafountaine, Jonathan M. Miller, Eric A. Schmitt.
Application Number | 20110306632 13/154562 |
Document ID | / |
Family ID | 44475097 |
Filed Date | 2011-12-15 |
United States Patent
Application |
20110306632 |
Kind Code |
A1 |
Miller; Jonathan M. ; et
al. |
December 15, 2011 |
Solid Dispersions Containing Kinase Inhibitors
Abstract
A solid dispersion comprises, in essentially non-crystalline
form, a kinase inhibitory compound, e.g.,
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea, dispersed in a solid matrix
that comprises (a) a pharmaceutically acceptable water-soluble
polymeric carrier and (b) a pharmaceutically acceptable surfactant.
A process for preparing such a solid dispersion comprises
dissolving the compound, the polymeric carrier and the surfactant
in a suitable solvent, and removing the solvent to provide a solid
matrix comprising the polymeric carrier and the surfactant and
having the compound dispersed in essentially non-crystalline form
therein. The solid dispersion is suitable for oral administration
to a subject in need thereof for treatment of a cancer.
Inventors: |
Miller; Jonathan M.;
(Lindenhurst, IL) ; Gokhale; Rajeev; (Sudan,
SG) ; Schmitt; Eric A.; (Libertyville, IL) ;
Gao; Yi; (Vernon Hills, IL) ; Lafountaine;
Justin; (Chicago, IL) ; Dias; Lloyd; (Gurnee,
IL) |
Assignee: |
ABBOTT LABORATORIES
Abbott Park
IL
|
Family ID: |
44475097 |
Appl. No.: |
13/154562 |
Filed: |
June 7, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61352862 |
Jun 9, 2010 |
|
|
|
Current U.S.
Class: |
514/293 ;
546/83 |
Current CPC
Class: |
A61K 9/145 20130101;
A61K 9/1652 20130101; A61K 9/2077 20130101; A61P 35/00 20180101;
A61K 9/1617 20130101; A61K 9/1635 20130101; A61K 9/146 20130101;
A61K 31/4743 20130101; A61K 9/1641 20130101; A61P 43/00
20180101 |
Class at
Publication: |
514/293 ;
546/83 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61P 35/00 20060101 A61P035/00; C07D 495/14 20060101
C07D495/14 |
Claims
1. A solid dispersion product comprising
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno
[3,2-c]pyridin-3-yl}phenyl)-N'-(3-fluorophenyl)urea or a
pharmaceutically acceptable salt thereof, at least one
pharmaceutically acceptable water-soluble polymeric carrier, and at
least one pharmaceutically acceptable surfactant.
2. The solid dispersion product of claim 1, wherein solid
dispersion product is amorphous.
3. The solid dispersion product of claim 1, comprising at least one
acid.
4. The solid dispersion product of claim 1, wherein the
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea is present in about 1% to
about 40% by free base equivalent weight.
5. The solid dispersion product of claim 4, wherein the
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea is present in about 5% to
about 15% by free base equivalent weight.
6. The solid dispersion product of claim 4, wherein the
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea is present in about 8% to
about 12% by free base equivalent weight.
7. The solid dispersion product of claim 3, wherein the at least
one acid comprises from about 0.1 to about 10 equivalents with
respect to
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno
[3,2-c]pyridin-3-yl}phenyl)-N'-(3-fluorophenyl)urea.
8. The solid dispersion product of claim 3, wherein the at least
one acid is selected from the group consisting of acetic acid,
ascorbic acid, benzenesulfonic acid, citric acid, ethanedisulfonic
acid, 1-hydroxy-2-napthoic acid, hydrochloric acid, hydrobromic
acid, lactic acid, maleic acid, malic acid, malonic acid,
methanesulfonic acid, phosphoric acid, sulfuric acid, succinic
acid, tartaric acid, and toluenesulfonic acid.
9. The solid dispersion product of claim 3, wherein the at least
one acid is selected from the group consisting of citric acid,
maleic acid, malic acid, malonic acid, succinic acid, and tartaric
acid.
10. The solid dispersion product of claim 3, wherein the at least
one acid is citric acid.
11. The solid dispersion product of claim 1, wherein the at least
one polymeric carrier is present in an amount of about 40% to about
85% by weight and the at least one surfactant is present in an
amount of about 5% to about 30% by weight.
12. The solid dispersion product of claim 1, wherein at least one
polymeric carrier is selected from the group consisting of
homopolymers and copolymers of N-vinyl lactams, cellulose esters,
cellulose ethers, high molecular weight polyalkylene oxides,
polyacrylates, polymethacrylates, polyacrylamides, vinyl acetate
polymers, oligo- and polysaccharides, and mixtures thereof.
13. The solid dispersion product of claim 1, wherein the at least
one polymeric carrier is selected from the group consisting of
polyvinylpyrrolidone, hydroxypropyl methylcellulose, and mixtures
thereof.
14. The solid dispersion product of claim 1, wherein the at least
one surfactant is selected from the group consisting of
polyethylene glycol glyceride derivatives, polyoxyethylene castor
oil derivatives, fatty acid monoesters of sorbitan, polysorbates,
poloxamers, .alpha.-tocopheryl polyethylene, glycol succinate, and
mixtures thereof.
15. The solid dispersion product of claim 1, wherein the at least
one surfactant is selected from the group consisting of
polysorbates, polyoxyethylene castor oil derivatives, and mixtures
thereof.
16. A process for preparing a solid dispersion product comprising:
a) forming a solution comprising (i)
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea or a pharmaceutically
acceptable salt thereof, (ii) a pharmaceutically acceptable acid,
(iii) at least one pharmaceutically acceptable water-soluble
polymeric carrier, (iv) at least one pharmaceutically acceptable
surfactant, and (v) at least one suitable solvent; and b) removing
the at least one solvent to provide a solid dispersion comprising
the at least polymeric carrier, the at least one surfactant, the at
least one acid, and having
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno
[3,2-c]pyridin-3-yl}phenyl)-N'-(3-fluorophenyl)urea or a
pharmaceutically acceptable salt thereof dispersed in an
essentially non-crystalline form therein.
17. The process of claim 16, comprising a combination of an aqueous
solvent and a water-miscible organic solvent.
18. The process of claim 17, wherein the organic solvent is
tetrahydrofuran, methanol, ethanol, or acetone.
19. The process of claim 16, wherein the solvent is removed by
spray-drying or under vacuum.
20. An orally deliverable pharmaceutical dosage form comprising the
solid dispersion product of claim 1.
21. The dosage form of claim 20, containing at least one additive
selected from the disintegrants, lubricants, and bulking
agents.
22. An orally deliverable pharmaceutical dosage form comprising the
solid dispersion product prepared by the process of claim 16.
23. The dosage form of claim 22, containing at least one additive
selected from the disintegrants, lubricants, and bulking
agents.
24. A method for treating cancer in a mammal comprising
administering to a subject having the disease a therapeutically
effective amount of the solid dispersion of claim 1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application Ser. No. 61/352,862 filed Jun. 9, 2010, which is
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to solid dispersions
comprising compounds that inhibit protein kinases, to
pharmaceutical dosage forms comprising such dispersions, to
processes for preparing such dispersions and dosage forms and to
methods of use thereof for treating diseases.
BACKGROUND OF THE INVENTION
[0003] Mitosis is a process by which a complete copy of a
duplicated genome is segregated by the microtuble spindle apparatus
into two daughter cells. Aurora-kinases, key mitotic regulators
required for genome stability, have been found to be overexpressed
in human tumors. There is therefore an existing need in the
therapeutic arts for compounds which inhibit Aurora-kinases,
compositions comprising the inhibitors and methods of treating
diseases during which Aurora-kinases are unregulated or
overexpressed.
[0004] The reversible phosphorylation of proteins is one of the
primary biochemical mechanisms mediating eukaryotic cell signaling.
This reaction is catalyzed by protein kinases that transfer the
g-phosphate group of ATP to hydroxyl groups on target proteins. 518
such enzymes exist in the human genome of which .about.90
selectively catalyze the phosphorylation of tyrosine hydroxyl
groups Cytosolic tyrosine kinases reside intracellularly whereas
receptor tyrosine kinases (RTKs) possess both extracellular and
intracellular domains and function as membrane spanning cell
surface receptors. As such, RTKs mediate the cellular responses to
environmental signals and facilitate a broad range of cellular
processes including proliferation, migration and survival.
[0005] RTK signaling pathways are normally highly regulated, yet
their over-activation has been shown to promote the growth,
survival and metastasis of cancer cells. Dysregulated RTK signaling
occurs through gene over-expression or mutation and has been
correlated with the progression of various human cancers.
[0006] The VEGF receptor (VEGFR) family consists of three RTKs, KDR
(kinase insert domain-containing receptor; VEGFR2), FLT1 (Fms-like
tyrosine kinase; VEGFR1), and FLT4 (VEGFR3). These receptors
mediate the biological function of the vascular endothelial growth
factors (VEGF-A, -B, -C, -D, -E and placenta growth factor (PlGF)),
a family of homodimeric glycoproteins that bind the VEGF receptors
with varying affinities.
[0007] KDR is the major mediator of the mitogenic, angiogenic and
permeability-enhancing effects of VEGF-A, hereafter referred to as
VEGF. Many different cell types are able to produce VEGF, yet its
biological activity is limited predominately to the vasculature by
way of the endothelial cell-selective expression of KDR. Not
surprisingly, the VEGF/KDR axis is a primary mediator of
angiogenesis, the means by which new blood vessels are formed from
preexisting vessels.
[0008] FLT1 binds VEGF, VEGF-B and placental growth factor. FLT1 is
expressed on the surface of smooth muscle cells, monocytes and
hematopoietic stems cells in addition to endothelial cells.
Activation of FLT1 signaling results in the mobilization of
marrow-derived endothelial progenitor cells that are recruited to
tumors where they contribute to new blood vessel formation.
[0009] FLT4 mediates the signaling of VEGF-C and VEGF-D, which
mediate formation of tumor-associated lymphatic vessels
(lymphangiogenesis). Lymphatic vessels are one of the routes by
which cancer cells disseminate from solid tumors during
metastasis.
[0010] The PDGF receptor (PDGFR) family consists of five RTK's,
PDGFR-a and -b, CSF1R, KIT, and FLT3.
[0011] CSF-1R is encoded by the cellular homolog of the retroviral
oncogene v-fms and is a major regulator of macrophage development.
Macrophages are frequent components of tumor stroma and have been
shown to modify the extracellular matrix in a manner beneficial to
tumor growth and metastasis.
[0012] KIT is expressed by hematopoietic progenitor cells, mast
cells, germ cells and by pacemaker cells in the gut (interstitial
cells of Cajal). It contributes to tumor progression by two general
mechanisms namely autocrine stimulation by its ligand, stem cell
factor (SCF), and through mutations that result in
ligand-independent kinase activity.
[0013] FLT3 is normally expressed on hematopoietic stem cells where
its interaction with FLT3 ligand (FL) stimulates stem cell
survival, proliferation and differentiation. In addition to being
over-expressed in various leukemia cells, FLT3 is frequently
mutated in hematological malignancies with approximately one-third
of patients with acute myeloid leukemia (AML) harboring activating
mutations.
[0014] The identification of effective small compounds which
specifically inhibit signal transduction and cellular proliferation
by modulating the activity of tyrosine kinases to regulate and
modulate abnormal or inappropriate cell proliferation,
differentiation, or metabolism is therefore desirable. In
particular, the identification of methods and compounds that
specifically inhibit the function of a tyrosine kinase which is
essential for angiogenic processes or the formation of vascular
hyperpermeability leading to edema, ascites, effusions, exudates,
and macromolecular extravasation and matrix deposition as well as
associated disorders would be beneficial.
[0015] Compounds that inhibit protein kinases such as
Aurora-kinases and the VEGFR and PDGFR families of kinases have
been identified. These compounds, and methods to make them, are
disclosed in U.S. Patent Publication No. 2007-0155776 A1
(hereinafter the '776 publication) and U.S. patent pplication Ser.
No. 12/632183 (hereinafter "the '183 application"), incorporated by
reference herein in their entirety.
[0016] The very low aqueous solubility of compounds, for example,
of the '183 application raises challenges for the formulator,
especially where there is a need to maintain acceptable oral
bioavailability, which is strongly dependent on solubility in the
aqueous medium of the gastrointestinal tract. Various solutions to
the challenge of low oral bioavailability have been proposed in the
art. For example, Sharma & Joshi (2007) Asian Journal of
Pharmaceutics 1(1):9-19 discuss various solubility enhancement
strategies in preparing solid dispersions. A solvent evaporation
method for preparing solid dispersions is described therein,
mentioning as an example a solid dispersion of etoricoxib, prepared
by a process that includes dissolving polyethylene glycol (PEG),
polyvinylpyrrolidone (PVP or povidone) and the active ingredient in
2-propanol.
[0017] To enhance clinical utility of an inhibitor of protein
kinases, for example as a chemotherapeutic in cancer patients, a
solid dosage form with acceptable oral bioavailability would be
highly desirable. Such a dosage form, and a regimen for oral
administration thereof, would represent an important advance in
treatment of many types of cancer, and would more readily enable
combination therapies with other chemotherapeutics.
SUMMARY OF THE INVENTION
[0018] There is now provided a solid dispersion product comprising
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3 -fluorophenyl)urea or a salt thereof, at least
one pharmaceutically acceptable water-soluble polymeric carrier,
and at least one pharmaceutically acceptable surfactant.
[0019] There is further provided a solid dispersion product
comprising
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno
[3,2-c]pyridin-3-yl}phenyl)-N'-(3-fluorophenyl)urea or a salt
thereof, at least one acid, at least one pharmaceutically
acceptable water-soluble polymeric carrier, and at least one
pharmaceutically acceptable surfactant.
[0020] There is further provided a solid dispersion product
comprising
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea, at least one acid, at least
one pharmaceutically acceptable water-soluble polymeric carrier,
and at least one pharmaceutically acceptable surfactant.
[0021] There is further provided a solid orally deliverable dosage
form comprising such a solid dispersion product, optionally
together with one or more additional excipients.
[0022] There is still further provided a process for preparing a
solid dispersion product as described above. This process
comprises:
[0023] (a) forming a solution comprising (i)
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea or salt thereof, (ii) a
pharmaceutically acceptable acid, (iii) at least one
pharmaceutically acceptable water-soluble polymeric carrier, (iv)
at least one pharmaceutically acceptable surfactant, and (v) at
least one suitable solvent; and
[0024] (b) removing the at least one solvent to provide a solid
dispersion comprising the at least polymeric carrier, the at least
one surfactant, the at least one acid, and having
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea dispersed in an essentially
non-crystalline form therein.
[0025] There is still further provided a solid dispersion prepared
by the process described above.
[0026] There is still further provided a method for treating cancer
comprising orally administering to a subject having the disease a
therapeutically effective amount of a solid dispersion as described
above, or one or more solid dosage forms comprising such a
dispersion.
[0027] There is further provided a solid dispersion product
comprising a kinase inhibitor, at least one pharmaceutically
acceptable water-soluble polymeric carrier, and at least one
pharmaceutically acceptable surfactant, wherein the solid
dispersion (a) remains amorphous for at least 1 month under open
storage at 25.degree. C. and 75% RH and (b) exhibits a glass
transition temperature at 75% RH of less than or equal to
15.degree. C. Preferably, the kinase inhibitor is
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea or a pharmaceutically
acceptable salt thereof.
[0028] Additional embodiments of the invention, including more
particular aspects of those provided above, will be found in, or
will be evident from, the detailed description that follows.
DETAILED DESCRIPTION
[0029] A solid dispersion in accordance with the present disclosure
comprises
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2--
c]pyridin-3-yl}phenyl)-N'-(3-fluorophenyl)urea or a
pharmaceutically acceptable salt thereof in an essentially
non-crystalline or amorphous form, which is usually more soluble
than the crystalline form. The term "solid dispersion" herein
encompasses systems having small solid-state particles of one phase
dispersed in another solid-state phase. More particularly, the
present solid dispersions comprise
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea dispersed in an inert
carrier.
[0030] An "amorphous form" refers to a particle without definite
structure, i.e., lacking crystalline structure.
[0031] The term "essentially non-crystalline" herein means that no
more than about 5%, for example no more than about 2%, or no more
than about 1% crystallinity is observed by X-ray diffraction
analysis. In a particular embodiment, no detectable crystallinity
is observed by one or both of X-ray diffraction analysis or
polarization microscopy.
[0032]
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]py-
ridin-3-yl}phenyl)-N'-(3-fluorophenyl)urea, including salts
thereof, typically have very low solubility in water, for example
less than about 100 mg/ml, in most cases less than about 30 mg/ml.
The present invention can be especially advantageous for drugs that
are essentially insoluble in water, i.e., having a solubility of
less than about 10 mg/ml, since a process of the invention
increases the apparent solubility of such a poorly-soluble active
ingredient. Examples of such active ingredients are, for example,
Biopharmaceutics Classification System (BCS) Class IV drug
substances that are characterized by low solubility and low
permeability (see "Waiver of in vivo bioavailability and
bioequivalence studies for immediate-release solid oral dosage
forms based on a biopharmaceutics classification system", U.S.
Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research (CDER),
August 2000). It will be recognized that aqueous solubility of many
compounds is pH-dependent; in the case of such compounds the
solubility of interest herein is at a physiologically relevant pH,
for example a pH of about 1 to about 8. Thus, in various
embodiments, the drug has a solubility in water, at least at one
point in a pH range from about 1 to about 8, of less than about 100
mg/ml, for example less than about 30 mg/ml, or less than about 10
.mu.g/ml. Illustratively,
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea has a solubility in water of
less than 30 ng/ml at pH 7.4.
[0033] Solid dispersions of the present invention comprise as
active ingredient
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea or a pharmaceutically
acceptable salt thereof. Optionally they may further comprise a
second active ingredient, for example a therapeutic agent useful in
combination therapy as indicated herein below.
[0034] The active ingredient
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea for use in this invention can
be crystalline or amorphous in its undispersed state.
[0035] The active ingredient
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea for use in this invention can
be in salt form or the non-salt free base.
[0036] For example, the active ingredient
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea may form acid addition salts.
Acid addition salts are those derived from reaction of a
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea with an acid. For example,
salts including the acetate, adipate, alginate, bicarbonate,
citrate, aspartate, benzoate, benzenesulfonate (besylate),
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
formate, fumarate, glycerophosphate, glutamate, hemisulfate,
heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,
lactobionate, lactate, maleate, mesitylenesulfonate,
methanesulfonate, naphthylenesulfonate, nicotinate, oxalate,
pamoate, pectinate, persulfate, phosphate, picrate, propionate,
succinate, tartrate, thiocyanate, trichloroacetate,
trifluoroacetate, para-toluenesulfonate and undecanoate salts of
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea can be used in a solid
dispersion of the invention.
[0037]
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]py-
ridin-3-yl}phenyl)-N'-(3-fluorophenyl)urea is prepared,
illustratively, as described in Example 1 of above-cited U.S.
patent application Ser. No. 12/632183, the entire disclosure of
which is incorporated by reference herein.
[0038]
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]py-
ridin-3-yl}phenyl)-N'-(3-fluorophenyl)urea is present in a solid
dispersion of the invention in an amount that can be
therapeutically effective when the composition is administered to a
subject in need thereof according to an appropriate regimen. Dosage
amounts are expressed herein as parent-compound-equivalent (free
base equivalent) amounts unless the context requires otherwise.
Typically, a unit dose (the amount administered at a single time),
which can be administered at an appropriate frequency, e.g., twice
daily to once weekly, is about 10 to about 1,000 mg, depending on
the compound in question. Where frequency of administration is once
daily (q.d.), unit dose and daily dose are the same.
Illustratively, the unit dose is typically about 25 to about 1,000
mg, more typically about 50 to about 500 mg, for example about 50,
about 100, about 150, about 200, about 250, about 300, about 350,
about 400, about 450 or about 500 mg. Where the dosage form
comprises a capsule shell enclosing the solid dispersion, a unit
dose can be deliverable in a single capsule or a plurality of
capsules, most typically 1 to about 10 capsules.
[0039] The higher the unit dose, the more desirable it becomes to
prepare a solid dispersion having a relatively high concentration
of the drug therein. Typically, the concentration of drug in the
solid dispersion is at least about 1%, e.g., about 1% to about 50%,
by free base equivalent weight, but lower and higher concentrations
can be acceptable or achievable in specific cases. The drug
concentration in various embodiments is at least about 1%, e.g.,
about 1% to about 40%, or at least about 5%, e.g., about 5% to
about 15%, or about 8%, e.g., about 8% to about 12% by free base
equivalent weight.
[0040] In some embodiments of the invention, the solid dispersion
product of the invention comprises at least one acid. The at least
one acid is selected from the group consisting of citric acid,
tartaric acid, succinic acid, malic acid, acetic acid, maleic acid,
malonic acid, ascorbic acid, lactic acid, sulfuric acid, phosphoric
acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid,
benznesulfonic acid, toluenesulfonic acid, ethanedisulfonic acid,
naphthalenesulfonic acid, and 1-hydroxy-2-napthoic acid. In a
preferred embodiment, the at least one acid is citric acid.
[0041] The at least one acid typically constitute in total about
0.1 to about 10 equivalents with respect to N-(4-
{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}-
phenyl)-N'-(3-fluorophenyl)urea, e.g., about 0.1 or more, about 0.5
or more, about 1 or more, or about 2 or more, or about 5 or more
equivalents.
[0042] The major component of the matrix of a solid dispersion
product is a polymer that is hydrophilic or water-soluble at least
in a part of the pH scale, more particularly at a pH occurring in
the gastrointestinal (GI) tract, or a combination of such polymers.
A polymer or polymer mixture useful herein is solid at ambient
temperature and, in the interests of good storage stability at a
range of temperatures, should remain solid even at the highest
temperatures typically experienced during storage, transport and
handling of the product. A useful property of a polymer determining
its usefulness herein is therefore its glass transition temperature
(T.sub.g). Suitable water-soluble polymers include, but are not
limited to, those having a T.sub.g of at least about 50.degree. C.,
more particularly about 80.degree. C. to about 180.degree. C.
Methods for determining T.sub.g values of organic polymers are
described for example in Sperling, ed. (1992) Introduction To
Physical Polymer Science, 2nd edition, John Wiley & Sons,
Inc.
[0043] Non-limiting examples of polymeric carriers useful herein
include:
[0044] homopolymers and copolymers of N-vinyl lactams, especially
homopolymers and copolymers of N-vinyl pyrrolidone, e.g., the
homopolymer polyvinylpyrrolidone (PVP or povidone, e.g.,
Kollidon.RTM. 12 PF or equivalent thereof, Kollidon.RTM. 17 PF or
equivalent thereof, Kollidon.RTM. 25 or equivalent thereof,
Kollidon.RTM. 30 or equivalent thereof, Kollidon.RTM. 90 F or
equivalent thereof) and copolymers such as those comprising
monomers of N-vinyl pyrrolidone and vinyl acetate (copovidone) or
N-vinyl pyrrolidone and vinyl propionate;
[0045] cellulose esters and cellulose ethers, in particular
methylcellulose, ethylcellulose, (hydroxyalkyl)celluloses such as
hydroxypropylcellulose, (hydroxyalkyl)alkyl-celluloses such as
hydroxypropylmethylcellulose (HPMC or hypromellose, e.g.,
Methocel.TM. E3 or equivalent thereof, Methocel.TM. E5 or
equivalent thereof, Methocel.TM. E6 or equivalent thereof,
Methocel.TM. E15 or equivalent thereof, Methocel.TM. K3 or
equivalent thereof,), cellulose phthalates and succinates such as
cellulose acetate phthalate, hydroxypropylmethylcellulose
phthalate, hydroxypropylmethylcellulose succinate and
hydroxypropylmethylcellulose acetate succinate (HPMC-AS);
[0046] high molecular weight polyalkylene oxides such as
polyethylene oxide, polypropylene oxide and copolymers of ethylene
oxide and propylene oxide (poloxamers);
[0047] polyacrylates and polymethacrylates such as methacrylic
acid/ethyl acrylate copolymers, methacrylic acid/methyl
methacrylate copolymers, butyl methacrylate/2-dimethylaminoethyl
methacrylate copolymers, poly(hydroxyalkyl acrylates) and
poly(hydroxyalkyl methacrylates);
[0048] polyacrylamides;
[0049] vinyl acetate polymers such as copolymers of vinyl acetate
and crotonic acid, partially hydrolyzed polyvinyl acetate (also
referred to as partially saponified "polyvinyl alcohol") and
polyvinyl alcohol;
[0050] oligo- and polysaccharides such as carrageenans,
galactomannans and xanthan gum;
and mixtures of two or more thereof.
[0051] In one embodiment, the solid dispersion matrix comprises one
or more polymeric carriers selected from the group consisting of
polyvinylpyrrolidone, hydroxypropyl methylcellulose, and mixtures
thereof. A particular example of a useful copovidone is one
consisting of about 60% N-vinyl pyrrolidone and about 40% vinyl
acetate monomers. A particular example of a useful povidone is one
having a K-value (a measure of viscosity of an aqueous solution of
the povidone) of about 30.
[0052] One or more polymeric carriers typically constitute in total
about 20% to about 90%, for example about 40% to about 85%, by
weight of the solid dispersion.
[0053] Upon oral administration and exposure to GI fluid, it is
believed without being bound by theory that, through interplay
between the polymeric carrier and a surfactant component of the
solid dispersion, a suitable release rate and inhibition of
crystallization or recrystallization of the active ingredient are
provided, thereby permitting bioabsorption.
[0054] Particularly useful as surfactants herein are
pharmaceutically acceptable non-ionic surfactants, especially those
having a hydrophilic-lipophilic balance (HLB) value of about 12 to
about 18, for example about 13 to about 17, or about 14 to about
16. The HLB system (see Fiedler (2002) Encyclopedia of Excipients,
5th edition, Aulendorf: ECV-Editio-Cantor-Verlag) attributes
numeric values to surfactants, with lipophilic substances receiving
lower HLB values and hydrophilic substances receiving higher HLB
values.
[0055] Non-limiting examples of non-ionic surfactants useful herein
include:
[0056] polyoxyethylene castor oil derivatives such as PEG-35 castor
oil (e.g., Cremophor.RTM. EL of BASF Corp. or equivalent product),
PEG-40 hydrogenated castor oil (e.g., Cremophor.RTM. RH40 or
equivalent product) and PEG-60 hydrogenated castor oil (e.g.,
Cremophor.RTM. RH 60 or equivalent product);
[0057] fatty acid monoesters of sorbitan, for example sorbitan
monooleate (e.g., Span.RTM. 80 or equivalent product), sorbitan
monostearate (e.g., Span.RTM. 60 or equivalent product), sorbitan
monopalmitate (e.g., Span.RTM. 40 or equivalent product) and
sorbitan monolaurate (e.g., Span.RTM. 20 or equivalent
product);
[0058] fatty acid monoesters of polyoxyethylene sorbitan
(polysorbates) such as PEG-20 sorbitan monooleate (polysorbate 80,
e.g., Tween.RTM. 80 or equivalent product) PEG-20 sorbitan
monostearate (polysorbate 60, e.g., Tween.RTM. 60 or equivalent
product), PEG-20 sorbitan monopalmitate (polysorbate 40, e.g.,
Tween.RTM. 40 or equivalent product), or PEG-20 sorbitan
monolaurate (polysorbate 20, e.g., Tween.TM. 20 or equivalent
product);
[0059] poloxamers such as poloxamer 124, poloxamer 188, poloxamer
237, poloxamer 388 or poloxamer 407;
[0060] polyethylene glycol glycerides composed of mono-, di- and
triglycerides and mono- and diesters of polyethylene glycol (e.g.
Gelucire.RTM. 44/14 or equivalent product and Gelucire.RTM. 50/13
or equivalent product)
[0061] .alpha.-tocopheryl polyethylene glycol succinate (TPGS or
vitamin E polyethylene glycol succinate, see U.S. National
Formulary);
and mixtures of two or more thereof.
[0062] One or more surfactants typically constitute in total about
2% to about 40%, for example about 5% to about 30%, by weight of
the solid dispersion.
[0063] The solid dispersions of the present invention are stable,
i.e., the solid dispersion remains amorphous. It is critical that
the amorphous solid dispersions do not change form over time and
potentially affect the drug product's performance. Therefore, in
yet another embodiment, there is further provided a solid
dispersion product comprising a kinase inhibitor, at least one
pharmaceutically acceptable water-soluble polymeric carrier, and at
least one pharmaceutically acceptable surfactant, wherein the solid
dispersion (a) remains amorphous for at least 1 month under open
storage at 25.degree. C. and 75% RH and (b) exhibits a glass
transition temperature at 75% RH of less than or equal to
15.degree. C. Preferably, the kinase inhibitor is
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea or a pharmaceutically
acceptable salt thereof.
[0064] A dosage form of the invention can consist of, or consist
essentially of, a solid dispersion as described above. However, in
some embodiments a dosage form contains additional excipients and
requires additional processing of the solid dispersion. For
example, the solid dispersion can be ground to a powder and filled
into a capsule shell or molded or compressed to form a tablet, with
additional excipients as may be conventionally used in such dosage
forms.
[0065] Thus orally deliverable solid dosage forms of the invention
include but are not limited to capsules, dragees, granules, pills,
powders and tablets. Excipients commonly used to formulate such
dosage forms include encapsulating materials or formulation
additives such as absorption accelerators, antioxidants, binders,
buffers, coating agents, coloring agents, diluents, disintegrating
agents, emulsifiers, extenders, fillers, flavoring agents,
humectants, lubricants, preservatives, propellants, releasing
agents, sterilizing agents, sweeteners, solubilizers and mixtures
thereof. Examples of specific excipients include agar, alginic
acid, aluminum hydroxide, benzyl benzoate, 1,3-butylene glycol,
castor oil, cellulose, cellulose acetate, cocoa butter, corn
starch, corn oil, cottonseed oil, ethanol, ethyl acetate, ethyl
carbonate, ethyl cellulose, ethyl laureate, ethyl oleate, gelatin,
germ oil, glucose, glycerol, groundnut oil, isopropanol, isotonic
saline, lactose, magnesium hydroxide, magnesium stearate, malt,
olive oil, peanut oil, potassium phosphate salts, potato starch,
propylene glycol, talc, tragacanth, water, safflower oil, sesame
oil, sodium carboxymethyl cellulose, sodium lauryl sulfate, sodium
phosphate salts, soybean oil, sucrose, tetrahydrofurfuryl alcohol,
and mixtures thereof.
[0066] In one embodiment, the orally deliverable solid dosage form
of the invention is a tablet containing solid dispersion powder,
filler, disintegrant, glidant and lubricant. In another embodiment,
the tablet contains 50% by weight of the solid dispersion
powder.
[0067] A process for preparing a solid dispersion as described
above comprises forming a solution comprising
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea or a salt thereof, the acid,
the polymeric carrier and the surfactant in at least one suitable
solvent; and removing the solvent to provide the solid
dispersion.
[0068] Alternatively, a process for preparing a solid dispersion as
described above comprises forming a solution comprising
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea or a salt thereof, the
polymeric carrier and the surfactant in at least one suitable
solvent; and removing the solvent to provide the solid
dispersion.
[0069] In yet another embodiment, a process for preparing a solid
dispersion as described above comprises forming a solution
comprising
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea, the acid, the polymeric
carrier and the surfactant in at least one suitable solvent; and
removing the solvent to provide the solid dispersion.
[0070] In the forming step, the various components can be added in
any order. For example, each ingredient can be added to the solvent
separately and then dissolved therein. Alternatively, the polymeric
carrier and/or surfactant can be pre-mixed with the
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea, and the resulting mixture
then added to the solvent or the solvent added to the resulting
mixture. Alternatively,
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea and the acid can be added to
the at least one solvent, then add the polymeric carrier and
surfactant.
[0071] In principle any solvent can be used so long as it is
effective to dissolve the active ingredient, polymer carrier and
surfactant. Non-limiting examples of solvents that can be useful
include methanol, ethanol, acetone, tetrahydrofuran, water and
mixtures thereof. In a preferred embodiment, a combination of an
aqueous solvent and a water-miscible organic solvent is used.
Preferably, the components are dissolved in a mixture of water and
acetone or a mixture of water and tetrahydrofuran.
[0072] Solvent removal can be accomplished using heat, vacuum or a
combination thereof. If heat is used, it is generally preferable to
avoid exceeding the glass transition temperature (T.sub.g) of the
polymeric matrix. For most purposes heating at a temperature of
about 50.degree. C. to about 80.degree. C., for example about
55.degree. C. to about 75.degree. C., will be found suitable. After
solvent removal, the resulting product is cooled (if necessary) to
ambient temperature.
[0073] Further process details can be found in the illustrative
processes of Example 1 below.
[0074] The terms "orally deliverable", "oral administration" and
"orally administered" herein refer to administration to a subject
per os (p.o.), that is, administration wherein the composition is
immediately swallowed, for example with the aid of a suitable
volume of water or other potable liquid. "Oral administration" is
distinguished herein from intraoral administration, e.g.,
sublingual or buccal administration or topical administration to
intraoral tissues such as periodontal tissues, that does not
involve immediate swallowing of the composition.
[0075] The invention provides a solid dispersion or dosage form
having acceptable bioabsorption when administered orally. Such
bioabsorption can be evidenced, for example, by the pharmacokinetic
(PK) profile of the solid dispersion or dosage form, more
particularly by the C.sub.max or AUC, for example AUC.sub.0-24 or
AUC.sub.0-.infin. at a particular dose or over a range of doses.
Illustratively, bioavailability can be expressed as a percentage,
for example using the parameter F, which computes AUC for oral
delivery of a test composition as a percentage of AUC for
intravenous (i.v.) delivery of the drug in a suitable solvent,
taking into account any difference between oral and i.v. doses.
[0076] Bioavailability can be determined by PK studies in humans or
in any suitable model species. For present purposes, a dog model,
as illustratively described in Example 2 below, is generally
suitable. In various illustrative embodiments, where the drug is
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea, compositions of the invention
exhibit oral bioavailability of at least about 15%, at least about
20%, at least about 25% or at least about 30%, up to or exceeding
about 50%, in a dog model, when administered as a single dose of
about 2.5 to about 50 mg/kg to fasting or non-fasting animals.
[0077] Compositions embraced herein, including compositions
described generally or with specificity herein, are useful for
orally delivering
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea to a subject. Accordingly, a
method of the invention for delivering such a drug to a subject
comprises orally administering a composition as described
above.
[0078] The subject can be human or non-human (e.g., a farm, zoo,
work or companion animal, or a laboratory animal used as a model)
but in an important embodiment the subject is a human patient in
need of the drug, for example to treat cancer. A human subject can
be male or female and of any age, but is typically an adult.
[0079] The composition is normally administered in an amount
providing a therapeutically effective daily dose of the drug. The
term "daily dose" herein means the amount of drug administered per
day, regardless of the frequency of administration. For example, if
the subject receives a unit dose of 150 mg twice daily, the daily
dose is 300 mg. Use of the term "daily dose" will be understood not
to imply that the specified dosage amount is necessarily
administered once daily. However, in a particular embodiment the
dosing frequency is once daily (q.d.), and the daily dose and unit
dose are in this embodiment the same thing.
[0080] What constitutes a therapeutically effective dose depends on
the particular compound, the subject (including species and body
weight of the subject), the disease (e.g., the particular type of
cancer) to be treated, the stage and/or severity of the disease,
the individual subject's tolerance of the compound, whether the
compound is administered in monotherapy or in combination with one
or more other drugs, e.g., other chemotherapeutics for treatment of
cancer, and other factors. Thus the daily dose can vary within wide
margins, for example from about 10 to about 1,000 mg. Greater or
lesser daily doses can be appropriate in specific situations. It
will be understood that recitation herein of a "therapeutically
effective" dose herein does not necessarily require that the drug
be therapeutically effective if only a single such dose is
administered; typically therapeutic efficacy depends on the
composition being administered repeatedly according to a regimen
involving appropriate frequency and duration of administration. It
is strongly preferred that, while the daily dose selected is
sufficient to provide benefit in terms of treating the cancer, it
should not be sufficient to provoke an adverse side-effect to an
unacceptable or intolerable degree. A suitable therapeutically
effective dose can be selected by the physician of ordinary skill
without undue experimentation based on the disclosure herein and on
art cited herein, taking into account factors such as those
mentioned above. The physician may, for example, start a cancer
patient on a course of therapy with a relatively low daily dose and
titrate the dose upwards over a period of days or weeks, to reduce
risk of adverse side-effects.
[0081] Illustratively, suitable doses of
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea are generally about 10 to
about 1,000 mg/day, more typically about 50 to about 500 mg/day or
about 200 to about 400 mg/day, for example about 50, about 100,
about 150, about 200, about 250, about 300, about 350, about 400,
about 450 or about 500 mg/day, administered at an average dosage
interval of 3 to 10 days, or about 4 to 8 days, or about 7
days.
[0082] Where the composition is in the form of a capsule, one to a
small plurality of capsules can be swallowed whole, typically with
the aid of water or other imbibable liquid to help the swallowing
process. Suitable capsule shell materials include, without
limitation, gelatin (in the form of hard gelatin capsules or soft
elastic gelatin capsules), starch, carrageenan and HPMC.
[0083] As compositions of the present invention are believed to
exhibit only a minor food effect, administration according to the
present embodiment can be with or without food, i.e., in a
non-fasting or fasting condition. It is generally preferred to
administer the present compositions to a non-fasting patient.
[0084] Compositions of the invention are suitable for use in
monotherapy or in combination therapy, for example with other
chemotherapeutics or with ionizing radiation. A particular
advantage of the present invention is that it permits once-daily
oral administration, a regimen which is convenient for the patient
who is undergoing treatment with other orally administered drugs on
a once-daily regimen. Oral administration is easily accomplished by
the patient him/herself or by a caregiver in the patient's home; it
is also a convenient route of administration for patients in a
hospital or residential care setting.
[0085] A composition of the invention, for example such a
composition comprising
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea, can be administered in
combination therapy with one or more therapeutic agents that
include, but are not limited to, alkylating agents, angiogenesis
inhibitors, antibodies, antimetabolites, antimitotics,
antiproliferatives, antivirals, aurora kinase inhibitors, other
apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1
inhibitors), activators of a death receptor pathway, Bcr-Abl kinase
inhibitors, BiTE (bi-specific T-cell engager) antibodies,
antibody-drug conjugates, biological response modifiers,
cyclin-dependent kinase (CDK) inhibitors, cell cycle inhibitors,
cyclooxygenase-2 (COX-2) inhibitors, dual variable domain binding
proteins (DVDs), human epidermal growth factor receptor 2 (ErbB2 or
HER/2neu) receptor inhibitors, growth factor inhibitors, heat shock
protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors,
hormonal therapies, immunologicals, inhibitors of apoptosis
proteins (IAPs), intercalating antibiotics, kinase inhibitors,
kinesin inhibitors, JAK2 inhibitors, mammalian target of rapamycin
(mTOR) inhibitors, microRNAs, mitogen-activated extracellular
signal-regulated kinase (MEK) inhibitors, multivalent binding
proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly-ADP
(adenosine diphosphate)-ribose polymerase (PARP) inhibitors,
platinum chemotherapeutics, polo-like kinase (Plk) inhibitors,
phosphoinositide-3 kinase (PI3K) inhibitors, proteasome inhibitors,
purine analogs, pyrimidine analogs, receptor tyrosine kinase
inhibitors, retinoids, deltoids, plant alkaloids, small inhibitory
ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin
ligase inhibitors, and the like.
[0086] BiTE antibodies are bi-specific antibodies that direct
T-cells to attack cancer cells by simultaneously binding the two
cells. The T-cell then attacks the target cancer cell. Examples of
BiTE antibodies include, but are not limited to, adecatumumab
(Micromet MT201), blinatumomab (Micromet MT103) and the like.
Without being limited by theory, one of the mechanisms by which
T-cells elicit apoptosis of the target cancer cell is by exocytosis
of cytolytic granule components, which include perforin and
granzyme B. In this regard, Bcl-2 has been shown to attenuate the
induction of apoptosis by both perforin and granzyme B. These data
suggest that inhibition of Bcl-2 could enhance the cytotoxic
effects elicited by T-cells when targeted to cancer cells (Sutton
et al. (1997) J. Immunol. 158:5783-5790).
[0087] SiRNAs are molecules having endogenous RNA bases or
chemically modified nucleotides. The modifications do not abolish
cellular activity, but rather impart increased stability and/or
increased cellular potency. Examples of chemical modifications
include phosphorothioate groups, 2'-deoxynucleotide,
2'-OCH.sub.3-containing ribonucleotides, 2'-F-ribonucleotides,
2'-methoxyethyl ribonucleotides, combinations thereof and the like.
The siRNA can have varying lengths (e.g., 10-200 bps) and
structures (e.g., hairpins, single/double strands, bulges,
nicks/gaps, mismatches) and are processed in cells to provide
active gene silencing. A double-stranded siRNA (dsRNA) can have the
same number of nucleotides on each strand (blunt ends) or
asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be
present on the sense and/or the antisense strand, as well as
present on the 5'- and/ or the 3'-ends of a given strand. For
example, siRNAs targeting Mcl-1 have been shown to enhance the
activity of ABT-263 or ABT-737 in various tumor cell lines (Tse et
al. (2008) Cancer Res. 68:3421-3428 and references therein).
[0088] Multivalent binding proteins are binding proteins comprising
two or more antigen binding sites. Multivalent binding proteins are
engineered to have the three or more antigen binding sites and are
generally not naturally occurring antibodies. The term
"multispecific binding protein" means a binding protein capable of
binding two or more related or unrelated targets. Dual variable
domain (DVD) binding proteins are tetravalent or multivalent
binding proteins binding proteins comprising two or more antigen
binding sites. Such DVDs may be monospecific (i.e., capable of
binding one antigen) or multispecific (i.e., capable of binding two
or more antigens). DVD binding proteins comprising two heavy-chain
DVD polypeptides and two light-chain DVD polypeptides are referred
to as DVD Ig's. Each half of a DVD Ig comprises a heavy-chain DVD
polypeptide, a light-chain DVD polypeptide, and two antigen binding
sites. Each binding site comprises a heavy -chain variable domain
and a light-chain variable domain with a total of 6 CDRs involved
in antigen binding per antigen binding site.
[0089] Alkylating agents include altretamine, AMD-473, AP-5280,
apaziquone, bendamustine, brostallicin, busulfan, carboquone,
carmustine (BCNU), chlorambucil, Cloretazine.TM. (laromustine, VNP
40101M), cyclophosphamide, dacarbazine, estramustine, fotemustine,
glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide,
melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard
N-oxide, ranimustine, temozolomide, thiotepa, treosulfan,
trofosfamide and the like.
[0090] Angiogenesis inhibitors include epidermal growth factor
receptor (EGFR) inhibitors, endothelial-specific receptor tyrosine
kinase (Tie-2) inhibitors, insulin growth factor-2 receptor
(IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors,
matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived
growth factor receptor (PDGFR) inhibitors, thrombospondin analogs,
vascular endothelial growth factor receptor tyrosine kinase (VEGFR)
inhibitors and the like.
[0091] Antimetabolites include Alimta.TM. (pemetrexed disodium,
LY231514, MTA), 5-azacitidine, Xeloda.TM. (capecitabine), carmofur,
Leustat.TM. (cladribine), clofarabine, cytarabine, cytarabine
ocfosfate, cytosine arabinoside, decitabine, deferoxamine,
doxifluridine, eflornithine, EICAR
(5-ethynyl-1-.beta.-D-ribofuranosylimidazole-4-carboxamide),
enocitabine, ethenylcytidine, fludarabine, 5-fluorouracil (5-FU)
alone or in combination with leucovorin, Gemzar.TM. (gemcitabine),
hydroxyurea, Alkeran.TM. (melphalan), mercaptopurine,
6-mercaptopurine riboside, methotrexate, mycophenolic acid,
nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,
raltitrexed, ribavirin, S-1, triapine, trimetrexate, TS-1,
tiazofurin, tegafur, vidarabine, UFT and the like.
[0092] Antivirals include ritonavir, hydroxychloroquine and the
like.
[0093] Aurora kinase inhibitors include AZD-1152, MLN-8054, VX-680,
aurora A-specific kinase inhibitors, aurora B-specific kinase
inhibitors, pan-aurora kinase inhibitors and the like.
[0094] Bcl-2 family protein inhibitors other than ABT-263 or
compounds of Formula I herein include AT-101 ((-)gossypol),
Genasense.TM. Bcl-2-targeting antisense oligonucleotide (G3139 or
oblimersen), IPI-194, IPI-565,
N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)
piperazin-l-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)met-
hyl)propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), GX-070
(obatoclax) and the like
[0095] Bcr-Abl kinase inhibitors include dasatinib (BMS-354825),
Gleevec.TM. (imatinib) and the like.
[0096] CDK inhibitors include AZD-5438, BMI-1040, BMS-387032,
CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509,
seliciclib (CYC-202 or R-roscovitine), ZK-304709 and the like.
[0097] COX-2 inhibitors include ABT-963, Arcoxia.TM. (etoricoxib),
Bextra.TM. (valdecoxib), BMS-347070, Celebrex.TM. (celecoxib),
COX-189 (lumiracoxib), CT-3, Deramaxx.TM. (deracoxib), JTE-522,
4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl)-1H-pyrrole,
MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125,
SD-8381, SVT-2016, S-2474, T-614, Vioxx.TM. (rofecoxib) and the
like.
[0098] EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes,
EGF-vaccine, EMD-7200, Erbitux.TM. (cetuximab), HR3, IgA
antibodies, Iressa.TM. (gefitinib), Tarceva.TM. (erlotinib or
OSI-774), TP-38, EGFR fusion protein, Tykerb.TM. (lapatinib) and
the like.
[0099] ErbB2 receptor inhibitors include CP-724714, CI-1033
(canertinib), Herceptin.TM. (trastuzumab), Tykerb.TM. (lapatinib),
Omnitarg.TM. (2C4, petuzumab), TAK-165, GW-572016 (ionafamib),
GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER2
vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2
trifunctional bispecific antibodies, mAB AR-209, mAB 2B-1 and the
like.
[0100] Histone deacetylase inhibitors include depsipeptide,
LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA),
TSA, valproic acid and the like.
[0101] HSP-90 inhibitors include 17AAG, CNF-101, CNF-1010,
CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, Mycograb.TM.
(human recombinant antibody to HSP-90), nab-17AAG, NCS-683664,
PU24FC1, PU-3, radicicol, SNX-2112, STA-9090, VER-49009 and the
like.
[0102] Inhibitors of apoptosis proteins include HGS-1029, GDC-0145,
GDC-0152, LCL-161, LBW-242 and the like.
[0103] Antibody-drug conjugates include anti-CD22-MC-MMAF,
anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC,
MEDI-547, SGN-19A, SGN-35, SGN-75 and the like.
[0104] Activators of death receptor pathway include TRAIL and
antibodies or other agents that target TRAIL or death receptors
(e.g., DR4 and DR5) such as apomab, conatumumab, ETR2-ST01, GDC0145
(lexatumumab), HGS-1029, LBY-135, PRO-1762, trastuzumab and the
like.
[0105] Kinesin inhibitors include Eg5 inhibitors such as AZD-4877
and ARRY-520, CENPE inhibitors such as GSK-923295A, and the
like.
[0106] JAK2 inhibitors include CEP-701 (lesaurtinib), XL019,
NCB-018424 and the like.
[0107] MEK inhibitors include ARRY-142886, ARRY-438162, PD-325901,
PD-98059 and the like.
[0108] mTOR inhibitors include AP-23573, CCI-779, everolimus,
RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2
inhibitors, including PI-103, PP242, PP30 and Torin 1, and the
like.
[0109] Non-steroidal anti-inflammatory drugs include Amigesic.TM.
(salsalate), Dolobid.TM. (diflunisal), Motrin.TM. (ibuprofen),
Orudis.TM. (ketoprofen), Relafen.TM. (nabumetone), Feldene.TM.
(piroxicam), ibuprofen cream, Aleve.TM. and Naprosyn.TM.
(naproxen), Voltaren.TM. (diclofenac), Indocin.TM. (indomethacin),
Clinoril.TM. (sulindac), Tolectin.TM. (tolmetin), Lodine.TM.
(etodolac), Toradol.TM. (ketorolac), Daypro.TM. (oxaprozin) and the
like.
[0110] PDGFR inhibitors include CP-673451, CP-868596 and the
like.
[0111] Platinum chemotherapeutics include cisplatin, Eloxatin.TM.
(oxaliplatin), eptaplatin, lobaplatin, nedaplatin, Paraplatin.TM.
(carboplatin), picoplatin, satraplatin and the like.
[0112] Polo-like kinase inhibitors include BI-2536 and the
like.
[0113] Phosphoinositide-3 kinase inhibitors include wortmannin,
LY-294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,
GDC-0941, BGT226, BEZ235, XL765 and the like.
[0114] Thrombospondin analogs include ABT-510, ABT-567, ABT-898,
TSP-1 and the like.
[0115] VEGFR inhibitors include Avastin.TM. (bevacizumab), ABT-869,
AEE-788, Angiozyme.TM. (a ribozyme that inhibits angiogenesis
(Ribozyme Pharmaceuticals (Boulder, Colo.) and Chiron (Emeryville,
Calif.)), axitinib (AG-13736), AZD-2171, CP-547632, IM-862,
Macugen.TM. (pegaptanib), Nexavar.TM. (sorafenib, BAY43-9006),
pazopanib (GW-786034), vatalanib (PTK-787 or ZK-222584), Sutent.TM.
(sunitinib or SU-11248), VEGF trap, Zactima.TM. (vandetanib or
ZD-6474) and the like.
[0116] Antibiotics include intercalating antibiotics such as
aclarubicin, actinomycin D, amrubicin, annamycin, Adriamycin.TM.
(doxorubicin), Blenoxane.TM. (bleomycin), daunorubicin, Caelyx.TM.
and Myocet.TM. (liposomal doxorubicin), elsamitrucin, epirubicin,
glarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin,
peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin,
Valstar.TM. (valrubicin), zinostatin and the like.
[0117] Topoisomerase inhibitors include aclarubicin,
9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan,
BN-80915, Camptosar.TM. (irinotecan hydrochloride), camptothecin,
Cardioxane.TM. (dexrazoxane), diflomotecan, edotecarin, Ellence.TM.
and Pharmorubicin.TM. (epirubicin), etoposide, exatecan,
10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone,
orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38,
tafluposide, topotecan and the like.
[0118] Antibodies include Avastin.TM. (bevacizumab), CD40-specific
antibodies, chTNT-1/B, denosumab, Erbitux.TM. (cetuximab),
Humax-CD4.TM. (zanolimumab), IGF1R-specific antibodies, lintuzumab,
Panorex.TM. (edrecolomab), Rencarex.TM. (WX G250), Rituxan.TM.
(rituximab), ticilimumab, trastuzumab, CD20 antibodies types I and
II and the like.
[0119] Hormonal therapies include Arimidex.TM. (anastrozole),
Aromasin.TM. (exemestane), arzoxifene, Casodex.TM. (bicalutamide),
Cetrotide.TM. (cetrorelix), degarelix, deslorelin, Desopan.TM.
(trilostane), dexamethasone, Drogenil.TM. (flutamide), Evista.TM.
(raloxifene), Afema.TM. (fadrozole), Fareston.TM. (toremifene),
Faslodex.TM. (fulvestrant), Femara.TM. (letrozole), formestane,
glucocorticoids, Hectorol.TM. (doxercalciferol), Renagel.TM.
(sevelamer carbonate), lasofoxifene, leuprolide acetate, Megace.TM.
(megestrol), Mifeprex.TM. (mifepristone), Nilandron.TM.
(nilutamide), tamoxifen including Nolvadex.TM. (tamoxifen citrate),
Plenaxis.TM. (abarelix), prednisone, Propecia.TM. (finasteride),
rilostane, Suprefact.TM. (buserelin), luteinizing hormone releasing
hormone (LHRH) including Trelstar.TM. (triptorelin), histrelin
including Vantas.TM. (histrelin implant), Modrastane.TM.
(trilostane), Zoladex.TM. (goserelin) and the like.
[0120] Deltoids and retinoids include seocalcitol (EB1089 or
CB1093), lexacalcitol (KH1060), fenretinide, Panretin.TM.
(alitretinoin), tretinoin including Atragen.TM. (liposomal
tretinoin), Targretin.TM. (bexarotene), LGD-1550 and the like.
[0121] PARP inhibitors include ABT-888, olaparib, KU-59436,
AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the
like.
[0122] Plant alkaloids include vincristine, vinblastine, vindesine,
vinorelbine and the like.
[0123] Proteasome inhibitors include Velcade.TM. (bortezomib),
MG132, NPI-0052, PR-171 and the like.
[0124] Examples of immunologicals include interferons and other
immune-enhancing agents. Interferons include interferon alpha,
interferon alpha-2a, interferon alpha-2b, interferon beta,
interferon gamma-1a, Actimmune.TM. (interferon gamma-1b),
interferon gamma-n1, combinations thereof and the like. Other
agents include Alfaferone (IFN-.alpha.), BAM-002 (oxidized
glutathione), Beromun.TM. (tasonermin), Bexxar.TM. (tositumomab),
Campath.TM. (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4),
dacarbazine, denileukin, epratuzumab, Granocyte.TM. (lenograstim),
lentinan, leukocyte alpha interferon, imiquimod, MDX-010
(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim,
Mylotarg.TM. (gemtuzumab ozogamicin), Neupogen.TM. (filgrastim),
OncoVAC-CL, Ovarex.TM. (oregovomab), pemtumomab (Y-muHMFG1),
Provenge.TM. (sipuleucel-T), sargaramostim, sizofiran, teceleukin,
Theracys.TM. (BCG or Bacillus Calmette-Guerin), ubenimex,
Virulizin.TM. (immunotherapeutic, Lorus Pharmaceuticals), Z-100
(Specific Substance of Maruyama or SSM), WF-10
(tetrachlorodecaoxide or TCDO), Proleukin.TM. (aldesleukin),
Zadaxin.TM. (thymalfasin), Zenapax.TM. (daclizumab), Zevalin.TM.
(90Y-ibritumomab tiuxetan) and the like.
[0125] Biological response modifiers are agents that modify defense
mechanisms of living organisms or biological responses, such as
survival, growth or differentiation of tissue cells to direct them
to have anti-tumor activity, and include krestin, lentinan,
sizofiran, picibanil, PF-3512676 (CpG-8954), ubenimex and the
like.
[0126] Pyrimidine analogs include cytarabine (cytosine arabinoside,
ara C or arabinoside C), doxifluridine, Fludara.TM. (fludarabine),
5-FU (5-fluorouracil), floxuridine, Gemzar.TM. (gemcitabine),
Tomudex.TM. (raltitrexed), triacetyluridine, Troxatyl.TM.
(troxacitabine) and the like.
[0127] Purine analogs include Lanvis.TM. (thioguanine),
Purinethol.TM. (mercaptopurine) and the like.
[0128] Antimitotic agents include batabulin, epothilone D
(KOS-862),
N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,
ixabepilone (BMS-247550), paclitaxel, Taxotere.TM. (docetaxel),
larotaxel (PNU-100940, RPR-109881 or XRP-9881), patupilone,
vinflunine, ZK-EPO (synthetic epothilone) and the like.
[0129] Ubiquitin ligase inhibitors include MDM2 inhibitors such as
nutlins, NEDD8 inhibitors such as MLN4924, and the like.
[0130] Compositions of this invention can also be used as
radiosensitizers that enhance the efficacy of radiotherapy.
Examples of radiotherapy include, but are not limited to, external
beam radiotherapy (XBRT), teletherapy, brachytherapy, sealed-source
radiotherapy, unsealed-source radiotherapy and the like.
[0131] Additionally or alternatively, a composition of the present
invention can be administered in combination therapy with one or
more antitumor or chemotherapeutic agents selected from
Abraxane.TM. (ABI-007), ABT-100 (farnesyl transferase inhibitor),
Advexin.TM. (Ad5CMV-p53 vaccine or contusugene ladenovec),
Altocor.TM. or Mevacor.TM. (lovastatin),
[0132] Ampligen.TM. (poly(I)-poly(C12U), a synthetic RNA),
Aptosyn.TM. (exisulind), Aredia.TM. (pamidronic acid), arglabin,
L-asparaginase, atamestane
(1-methyl-3,17-dione-androsta-1,4-diene), Avage.TM. (tazarotene),
AVE-8062 (combretastatin derivative), BEC2 (mitumomab), cachectin
or cachexin (tumor necrosis factor), Canvaxin.TM. (melanoma
vaccine), CeaVac.TM. (cancer vaccine), Celeuk.TM. (celmoleukin),
histamine including Ceplene.TM. (histamine dihydrochloride),
Cervarix.TM. (ASO4 adjuvant-adsorbed human papilloma virus (HPV)
vaccine), CHOP (Cytoxan.TM. (cyclophosphamide) +Adriamycin.TM.
(doxorubicin) +Oncovin.TM. (vincristine) +prednisone),
combretastatin A4P, Cypat.TM. (cyproterone), DAB(389)EGF (catalytic
and translocation domains of diphtheria toxin fused via a His-Ala
linker to human epidermal growth factor), dacarbazine,
dactinomycin, Dimericine.TM. (T4N5 liposome lotion),
5,6-dimethylxanthenone-4-acetic acid (DMXAA), discodermolide,
DX-8951f (exatecan mesylate), eniluracil (ethynyluracil),
squalamine including Evizon.TM. (squalamine lactate), enzastaurin,
EPO-906 (epothilone B), Gardasil.TM. (quadrivalent human papilloma
virus (Types 6, 11, 16, 18) recombinant vaccine), Gastrimmune.TM.,
Genasense.TM. (oblimersen), GMK (ganglioside conjugate vaccine),
GVAX.TM. (prostate cancer vaccine), halofuginone, histerelin,
hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38,
IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonas exotoxin,
interferon-.alpha., interferon-.gamma., Junovan.TM. and Mepact.TM.
(mifamurtide), lonafarnib, 5,10-methylenetetrahydrofolate,
miltefosine (hexadecylphosphocholine), Neovastat.TM. (AE-941),
Neutrexin.TM. (trimetrexate glucuronate), Nipent.TM. (pentostatin),
Onconase.TM. (ranpirnase, a ribonuclease enzyme), Oncophage.TM.
(vitespen, melanoma vaccine treatment), OncoVAX.TM. (IL-2 vaccine),
Orathecin.TM. (rubitecan), Osidem.TM. (antibody-based cell drug),
Ovarex.TM. MAb (murine monoclonal antibody), paclitaxel
albumin-stabilized nanoparticle, paclitaxel, Pandimex.TM. (aglycone
saponins from ginseng comprising 20(S)-protopanaxadiol (aPPD) and
20(S)-protopanaxatriol (aPPT)), panitumumab, Panvac.TM.
(investigational cancer vaccine), pegaspargase, peginterferon alfa
(PEG interferon A), phenoxodiol, procarbazine, rebimastat,
Removab.TM. (catumaxomab), Revlimid.TM. (lenalidomide), RSR13
(efaproxiral), Somatuline.TM. LA (lanreotide), Soriatane.TM.
(acitretin), staurosporine (Streptomyces staurospores), talabostat
(PT100), Targretin.TM. (bexarotene), Taxoprexin.TM.
(docosahexaenoic acid (DHA) +paclitaxel), Telcyta.TM.
(canfosfamide, TLK-286), Temodar.TM. (temozolomide), tesmilifene,
tetrandrine, thalidomide, Theratope.TM. (STn-KLH vaccine),
Thymitaq.TM. (nolatrexed dihydrochloride), TNFerade.TM.
(adenovector: DNA carrier containing the gene for tumor necrosis
factor-a), Tracleer.TM. or Zavesca.TM. (bosentan),
TransMID-107R.TM. (KSB-311, diphtheria toxins), tretinoin
(retin-A), Trisenox.TM. (arsenic trioxide), Ukrain.TM. (derivative
of alkaloids from the greater celandine plant), Virulizin.TM.,
Vitaxin.TM. (anti-.alpha.v.beta.3antibody), Xcytrin.TM. (motexafin
gadolinium), Xinlay.TM. (atrasentan), Xyotax.TM. (paclitaxel
poliglumex), Yondelis.TM. (trabectedin), ZD-6126
(N-acetylcolchinol-O-phosphate), Zinecard.TM. (dexrazoxane),
zoledronic acid, zorubicin and the like.
[0133] In one embodiment, a composition of the invention, for
example such a composition comprising
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin--
3-yl}phenyl)-N'-(3-fluorophenyl)urea or a salt thereof, is
administered in a therapeutically effective amount to a subject in
need thereof to treat cancer.
[0134] Examples include, but are not limited to, acoustic neuroma,
acute leukemia, acute lymphocytic leukemia, acute myelocytic
leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma,
astrocytoma, myelomonocytic and promyelocytic), acute t-cell
leukemia, basal cell carcinoma, bile duct carcinoma, bladder
cancer, brain cancer, breast cancer, bronchogenic carcinoma,
cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic
leukemia, chronic lymphocytic leukemia, chronic myelocytic
(granulocytic) leukemia, chronic myleogeneous leukemia, colon
cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,
diffuse large B-cell lymphoma, dysproliferative changes (dysplasias
and metaplasias), embryonal carcinoma, endometrial cancer,
endotheliosarcoma, ependymoma, epithelial carcinoma,
erythroleukemia, esophageal cancer, estrogen-receptor positive
breast cancer, essential thrombocythemia, Ewing's tumor,
fibrosarcoma, follicular lymphoma, germ cell testicular cancer,
glioma, heavy chain disease, hemangioblastoma, hepatoma,
hepatocellular cancer, hormone insensitive prostate cancer,
leiomyosarcoma, liposarcoma, lung cancer,
lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic
leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and
hyperproliferative disorders of the bladder, breast, colon, lung,
ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies
of T-cell or B-cell origin, leukemia, lymphoma, medullary
carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma,
multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma,
neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral
cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer,
papillary adenocarcinomas, papillary carcinoma, pinealoma,
polycythemia vera, prostate cancer, rectal cancer, renal cell
carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous
gland carcinoma, seminoma, skin cancer, small cell lung carcinoma,
solid tumors (carcinomas and sarcomas), small cell lung cancer,
stomach cancer, squamous cell carcinoma, synovioma, sweat gland
carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia,
testicular tumors, uterine cancer and Wilms' tumor in a mammal,
[0135] In a more particular embodiment, a composition of the
invention, is administered in a therapeutically effective amount to
a subject in need thereof to treat myelodysplastic syndrome, acute
myeloid leukemia, colorectal cancer, non-small cell lung cancer,
and ovarian cancer.
[0136] According to any of these embodiments, the composition is
administered in combination therapy with one or more additional
therapeutic agents.
[0137] As in other embodiments, administration according to the
present embodiment can be with or without food, i.e., in a
non-fasting or fasting condition. It is generally preferred to
administer the present compositions to a non-fasting patient.
EXAMPLES
[0138] The following examples are merely illustrative, and do not
limit this disclosure in any way. Trademarked ingredients used in
the examples, include:
[0139] Eudragit.RTM. L 100-55: Methacrylic Acid--Ethyl Acrylate
Copolymer;
[0140] Kollidon.RTM. VA64: vinylpyrrolidone-vinyl acetate
copolymer;
[0141] Kollidon.RTM. SR: polyvinyl acetate and povidone matrix;
[0142] Tween.RTM. 20: polysorbate 20 surfactant;
[0143] Cremophor.RTM. RH 40: Polyoxyl 40 Hydrogenated Castor
Oil
[0144] Gelucire.RTM. 44/14: polyethylene glycol glycerides
Example 1
Preparation of Solid Dispersions
[0145]
N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]py-
ridin-3-yl}phenyl)-N'-(3-fluorophenyl)urea free base (hereinafter
API) was mixed with an optional acid, surfactant(s) and
water-soluble polymer(s) in the following weight ratios: [0146]
Example 1A: 6% API:3.5% Citric Acid:20% Tween.RTM. 20:10% Poloxamer
124:60.5% PEG-1450 [0147] Example 1B: 10% API:6% Citric Acid:10%
Tween.RTM. 20:10% Poloxamer 124:24% HPMC-E5:40% PVP K17 [0148]
Example 1C: 6% API:3% Citric Acid:20% Tween.RTM. 20:71% PEG-1450
[0149] Example 1D: 7.5% API:4.5% Citric Acid, 10% Tween.RTM. 20:10%
Cremophor.RTM. RH 40:25% HPMC-E5: 43% PVP K17 [0150] Example 1E:
10% API:6% Citric Acid, 10% Tween.RTM. 20:10% Cremophor.RTM. RH
40:24% HPMC-E5:40% PVP K17 [0151] Example 1F: 5% API:3% Citric
Acid:20% Tween.RTM. 20:27% HPMC-E5:45% PVP K30 [0152] Example 1G:
5% API:6% Citric Acid:20% Tween.RTM. 20:24% HPMC-E5:40% PVP K30
[0153] Example 1H: 5% API:3% Citric Acid:20% Tween.RTM. 20:72%
HPMC-E5 [0154] Example 1I: 5% API:3% Citric Acid:20% Tween.RTM.
20:67% PEG-8000
[0155] Example 1J: 10% API:3% Citric Acid:10% Tween.RTM. 20:10%
Poloxamer 124:64% HPMC-E5 [0156] Example 1K: 5% API:2% Citric
Acid:10% Tween.RTM. 20:83% PEG-3350 [0157] Example 1L: 10% API:4%
Citric Acid:10% Tween.RTM. 20:76% HPMC E5 [0158] Example 1M: 10%
API, 20% Tween.RTM. 20:70% HPMC-AS L [0159] Example 1N: 5% API:3%
Citric Acid:25% Tween.RTM. 20:67% PEG-3350 [0160] Example 1O: 5%
API:2% Citric Acid:10% Tween.RTM. 20:83% PVP K30 [0161] Example 1P:
10% API:6% Citric Acid:10% Tween.RTM. 20:10% Poloxamer 124:64% PVP
K30 [0162] Example 1Q: 5% API:3% Citric Acid:20% Tween.RTM. 20:72%
PVP K30 [0163] Example 1R: 10% API:6% Citric Acid:10% Tween.RTM.
20:30% HPMC-E5:44% PVP K30 [0164] Example 1S: 5% API:4% Citric
Acid:91% Gelucire.RTM. 44/14 [0165] Example 1T: 12.5% API:7.5%
Citric Acid:20% Tween.RTM. 20:22.5% HPMC-E5:37.5% PVP K30 [0166]
Example 1U: 15% API:9% Citric Acid:20% Tween.RTM. 20:21%
HPMC-E5:35% PVP K30 [0167] Example 1V: 20% API:12% Citric Acid:20%
Tween.RTM. 20:18% HPMC-E5:30% PVP K30 [0168] Example 1W: 10% API:6%
Citric Acid:10% Tween.RTM. 20:10% Poloxamer 407:24% HPMC-E5:40% PVP
K17 [0169] Example 1X: 10% API:6% Citric Acid:10% Tween.RTM. 20:10%
Poloxamer 188:24% HPMC-E5:40% PVP-K17 [0170] Example 1Y: 5% API:2%
Citric Acid:10% Tween.RTM. 20:83% Eudragit.RTM. L 100-55 [0171]
Example 1Z: 10% API:6% Citric Acid:10% Tween.RTM. 20:10% Poloxamer
124:24% HPMC-E5:40% PVP K30 [0172] Example 1AA: 10% API:6% Citric
Acid:20% Tween.RTM. 20:24% HPMC-E3:40% PVP K30 [0173] Example 1AB
10T API:20% Tween.RTM. 20:70% HPMC-AS M [0174] Example 1AC: 10%
API:20% Tween.RTM. 20:70% HPMC-AS H [0175] Example 1AD: 10% API:6%
Citric Acid: 20% Tween.RTM. 20:24% HPMC-E3: 40% PVP K17 [0176]
Example 1AE: 10% API:6% Citric Acid:10% Tween.RTM. 20:10%
Gelucire.RTM. 44/14:24% HPMC-E5:40% PVP K17 [0177] Example 1AF: 5%
API:4% Citric Acid:91% Vitamin E TPGS [0178] Example 1AG: 10%
API:4% Citric Acid:10% Tween.RTM. 20:76% Kollidon.RTM. VA64 [0179]
Example 1AH: 10% API:7% Citric Acid:83% Kollidon.RTM. SR [0180]
Example 1AI: 10% API:6% Citric Acid:20% Tween.RTM. 20:24%
HPMC-K3:40% HPMC-K3 [0181] Example 1AJ: 5% API:2% Citric Acid:10%
Tween.RTM. 20:83% Kollidon.RTM. VA64 [0182] Example 1AK: 10% API:6%
Citric Acid:20% Tween.RTM. 20:24% HPMC-K3:40% PVP K30
[0183] The mixture of ingredients in each case were dissolved in
aqueous solvent and a water-miscible organic solvent, e.g., acetone
or tetrahydrofuran, between ambient temperature at 70.degree. C.
The solvent was removed by either rotary evaporation at 65.degree.
C. in vacuo or using a spray-dryer operating at 85.degree. C., and
the resulting solid dispersion was allowed to cool to ambient
temperature.
[0184] The solid dispersion in each case was sieved through a
30-mesh screen to provide a powder of reduced particle size. The
resulting solid dispersion was dried under vacuum at approximately
100.degree. C.
Example 2
Pharmacokinetics of Solids Dispersion in a Dog Model
[0185] Single-dose pharmacokinetics of the solid dispersions were
evaluated in fasted beagle dogs (n=3) after a 10, 25, or 50 mg oral
dose of solid dispersion in hard gelatin capsule followed by 10 ml
water. Approximately 30 min prior to drug administration, each dog
received a 100-mg/kg subcutaneous (sc) dose of histamine Food was
provided to the animals approximately 4 hours after dosing. Serial
heparinized blood samples were obtained from a jugular vein of each
animal prior to dosing and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 15
and 24 hours after administration. Plasma was separated by
centrifugation (2,000 rpm for 10 minutes at approximately 4.degree.
C.) and API was isolated using protein precipitation with
acetonitrile.
[0186] The area under the plasma concentration-time curve from 0 to
t hours (time of the last measured plasma concentration) after
dosing (AUC.sub.0-t) was calculated using the linear trapezoidal
rule for the plasma concentration-time profiles. The residual area
extrapolated to infinity, determined as the final measured plasma
concentration (C.sub.t) divided by the terminal elimination rate
constant (.beta.), was added to AUC.sub.0-t to produce the total
area under the curve (AUC.sub.0-.infin.). The bioavailability was
calculated as the dose-normalized AUC.sub.0-.infin. from oral
dosing divided by the corresponding value derived from i.v.
(intravenous) dosing, administered as a slow bolus to a jugular
vein under light ether anesthetic.
[0187] PK parameters for the dispersions are presented in Table
1.
TABLE-US-00001 TABLE 1 PK parameters of solid dispersion
compositions in dog (n = 3) C.sub.max/D AUC/D Dose C.sub.max
.mu.g/ml per AUC .mu.g h/ml Example mg T1/2 h .mu.g/ml mg/kg
T.sub.max h .mu.g h/ml per mg/kg F % 1A 10 5.2 0.50 0.46 2.0 2.8
2.6 30.8 1A 25 4.7 0.91 0.35 2.0 5.8 2.2 26.4 1A 50 5.4 2.16 0.41
2.8 14.0 2.6 31.2 1B 10 4.8 0.46 0.54 3.0 2.5 2.9 34.4 1B 25 5.1
0.90 0.41 2.8 5.3 2.4 28.1 1B 50 4.2 1.30 0.26 2.3 7.7 1.5 18.2 1C
10 4.7 0.37 0.43 2.8 1.9 2.2 25.9 1C 25 4.2 1.06 0.48 2.0 5.0 2.3
26.9 1C 50 4.3 1.82 0.38 2.0 8.9 1.8 21.7 1D 10 5.0 0.32 0.33 2.3
1.87 1.93 22.9 1D 25 5.1 0.87 0.39 2.1 4.11 1.84 21.8 1D 50 4.9
1.60 0.36 2.6 7.87 1.80 21.4 1E 10 5.1 0.38 0.36 2.7 2.4 2.3 26.1
1F 10 5.9 0.59 0.55 1.7 3.14 2.91 34.6 1G 10 5.9 0.41 0.39 2.5 2.7
2.6 29.5 1H 10 5.4 0.36 0.36 2.5 2.2 2.2 25.9 1I 10 6.9 0.35 0.33
2.7 2.3 2.2 25.7 1J 10 5.1 0.43 0.44 2.3 2.0 2.1 24.9 1K 10 4.3
0.28 0.28 3.3 2.1 2.1 24.4 1L 10 4.4 0.32 0.29 2.7 2.3 2.0 24.2 1M
10 6.1 0.44 0.40 3.0 2.2 1.98 23.5 1N 10 5.2 0.33 0.30 1.8 2.2 2.0
23.2 1O 10 4.8 0.35 0.34 3.3 2.0 1.92 22.8 1P 10 5.0 0.31 0.29 3.3
2.0 1.91 22.7 1Q 10 6.6 0.31 0.31 2.3 1.9 1.9 22.3 1R 10 4.8 0.26
0.30 2.3 1.6 1.8 21.3 1S 10 5.7 0.32 0.28 2.3 1.9 1.7 20.2 1T 10
9.0 0.32 0.31 1.8 1.77 1.67 19.9 1U 10 6.6 0.31 0.27 3.3 1.92 1.66
19.7 1V 10 7.2 0.36 0.34 2.2 1.68 1.58 18.8 1W 10 5.4 0.30 0.29 2.2
1.7 1.6 18.8 1X 10 5.3 0.33 0.33 3.0 1.6 1.6 18.6 1Y 10 4.5 0.43
0.38 2.5 1.8 1.56 18.5 1Z 10 4.8 0.27 0.26 1.3 1.5 1.47 17.5 1AA 10
4.5 0.30 0.27 3.0 1.6 1.4 17.0 1AB 10 3.3 0.29 0.30 2.3 1.4 1.42
16.9 1AC 10 5.6 0.21 0.20 2.5 1.4 1.32 15.7 1AD 10 5.1 0.19 0.18
2.2 1.3 1.3 14.5 1AE 10 3.8 0.24 0.24 3.7 1.2 1.2 14.3 1AF 10 7.9
0.21 0.19 1.7 1.3 1.2 14.0 1AG 10 4.0 0.13 0.14 3.0 1.07 1.10 13.1
1AH 10 5.4 0.15 0.15 2.3 0.9 0.88 10.4 1AI 10 4.0 0.15 0.15 3.3 0.9
0.9 10.2 1AJ 10 4.5 0.11 0.11 2.5 0.6 0.61 7.3 1AK 10 1.3 0.12 0.13
2.2 0.4 0.5 5.7
Example 3
Pharmacokinetics of Solids Dispersion in a Dog Model
[0188] Solid dispersion formulations of the invention were used in
an open-label Phase I human study evaluating the safety and
pharmacokinetics of
N-(4-{4-amino-7[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridi-
n-3-yl}phenyl)-N'-(3-fluorophenyl)urea as monotherapy in subjects
with advanced solid tumors or advanced hematologic
malignancies.
[0189] The number of subjects that entered the studies and
completed at least a portion of the studies are noted. Subjects
entered the study and were assigned to receive one of the following
doses: 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, and 180 mg. The
tablet formulation consisted of solid dispersion powder
corresponding to Example lE with excipients (50% Example 1E: 38.75%
microcrystalline cellulose: 10% crospovidone: 1% colloidal silicon
dioxide: 0.5% magnesium state).
[0190] Doses were administered on Day 1, Day 8, and Day 15 of each
28 day cycle. On Day 1 and Day 15, plasma samples are collected at
time 0, 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours or 0, 0.5, 1, 2, 3,
4, 6, 8, 10 or 12, 24, 48 and 72 hours after dosing. The plasma
concentrations of N-(4- {4-amino-7-
[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N'--
(3-fluorophenyl)urea were determined, and the values for the
pharmacokinetic parameters were calculated and shown in Table
2.
TABLE-US-00002 TABLE 2 PK parameters of solid dispersion
compositions in humans 10 mg 20 mg 40 mg 80 mg Pharmacokinetic Day
1 Day 15 Day 1 Day 15 Day 1 Day 15 Day 1 Day 15 Parameters (N = 6)
(N = 6) (N = 3) (N = 3) (N = 2) (N = 2) (N = 5) (N = 5) Terminal
Half-Life (h)* 15.0 .+-. 3.0 12.6 .+-. 4.4 15.5 .+-. 9.9 19.2 .+-.
6.0 9.8, NA 15.8, 11.5 15.3 .+-. 1.9 13.3 .+-. 4.2 T.sub.max (h)
3.3 .+-. 0.5 3.3 .+-. 0.8 4.0 .+-. 2.0 4.3 .+-. 1.5 3.0, 8.0 2.0,
3.0 3.0 .+-. 0.0 3.4 .+-. 1.7 C.sub.max (ng/mL)** 40.6 .+-. 25.3
26.9 .+-. 15.4 62.7 .+-. 78.3 58.4 .+-. 82.2 198, 43.7 247, 160 160
.+-. 70.6 98.4 .+-. 36.5 AUC.sub..infin. (.mu.g h/mL)** 0.62 .+-.
0.47 0.39 .+-. 0.17 1.11 .+-. 0.53 1.25 .+-. 1.30 1.83, NA 2.27,
1.64 1.85 .+-. 0.89 1.62 .+-. 0.82 AUC.sub.0-24 (.mu.g h/mL)** 0.40
.+-. 0.29.sup.a 0.27 .+-. 0.12.sup.a 0.34 .+-. 0.84.sup.b 0.47 .+-.
0.29.sup.b 1.51, 0.64 1.53, 1.15 1.05 .+-. 0.37.sup.c 1.04 .+-.
0.49.sup.c 120 mg 160 mg 180 mg Day 1 Day 15 Day 1 Day 15 Day 1 (N
= 7) (N = 4) (N = 3) (N = 3) (N = 3) Terminal Half-Life (h)* 9.7
.+-. 6.8.sup.a 20.4 .+-. 10.6.sup.d 14.3 .+-. 4.8 15.6 .+-. 3.3 9.2
.+-. 2.3 Tmax (h) 3.7 .+-. 2.1 4.3 .+-. 2.5 3.3 .+-. 1.2 2.3 .+-.
1.2 4.0 .+-. 2.02 Cmax (ng/mL)** 395 .+-. 272 208 .+-. 84.6 265
.+-. 198 178 .+-. 36.0 439 .+-. 354 AUC.infin. (.mu.g h/mL)** 4.93
.+-. 1.65.sup.a 4.17 .+-. 2.41.sup.d 3.0 .+-. 1.84 2.59 .+-. 0.77
6.61 .+-. 2.99 AUC.sub.0-24 (.mu.g h/mL)** 2.47 .+-. 0.20.sup.d
1.84 .+-. 0.35.sup.b 2.36 .+-. 1.34 1.75 .+-. 0.27 5.28 .+-.
2.35.sup.d *Harmonic Mean and Pseudo Standard Deviation **Geometric
mean .+-. Pseudo Standard Deviation .sup.aN = 5 .sup.bN = 2 .sup.cN
= 4 .sup.dN = 3 .sup.eN = 6
* * * * *